GABA modulation and negative affect in psychosis Schizophrenia frequently presents with clinically significant negative affect. In addition to co-morbid depression and anxiety disorders (up to 60 O/O), patients show high levels of trait negative affectivity. Anxiety and sensitivity to stress appear in the prodromal period and throughout the course of the illness, co-varying with positive symptoms of the illness, but also accounting for phenotypic variance and functional outcome independently of positive and deficit symptoms. Pharmacotherapy of negative affects, particularly anxiety, often augments GABAergic function with benzodiazepines (BDZ). BDZ's can also prevent a psychotic episode in the early stages of relapse, suggesting a link between GABAergic function and the genesis of psychosis. The clinical use of GABAergic augmentation is intriguing in light of post-mortem evidence of reduced GABAergic function of inhibitory cortical inter-neurons in schizophrenia. While GABA-A receptors are widespread, subtypes relevant for psychosis may have a more regionally-specific pattern of distribution. Exploiting the therapeutic leverage provided by a BDZ, this R21 proposal will focus on how BDZs modulate large-scale networks that process affective information. Validated tasks that tap affective appraisal networks will focus on the medial frontal cortex (MFC), a structure implicated in schizophrenia. Emerging data have shown excessive activity in the MFC of schizophrenic/schizoaffective(SCZ) patients processing negative emotional stimuli. The exploratory experiment in this proposal is designed to functionally identify circuits specific to chronic psychosis, as well as those general to anxiety. Twenty SCZ patients, 20 healthy controls (HC) and 20 patients with social phobia (SP) will be studied in a blinded cross-over design with intravenous lorazepam and placebo. They will perform two appraisal tasks (rating emotional pictures and judging personal preference for emotional faces) during functional magnetic resonance imaging. Comparing SCZ to HS and SP in Aim 1, we predict specific effects in the MFC during appraisal and after BDZ: greater attenuation of MFC activity, elicited by appraising negative stimuli, will be induced by BDZ for SCZ. In Aim 2, we will search for regions involved in affective appraisal, such as the anterior insula, attenuated by BDZ, and common to both groups with anxiety, i. e. decreases in SCZ &SP >HC. Aim 3 will explore network level changes induced by BDZ, specifically focusing on thalamocortical connectivity with the MFC. Identifying large- scale neurocircuits where a BDZ modulates the appraisal processes in SCZ may provide important clues to localize the GABA systems that are relevant to psychosis. Once identified, specific neurocircuits may be targeted with neuromodulatory interventions that can enhance inhibitory function, such as transcranial magnetic stimulation, providing new avenues for the treatment of this devastating brain disorder. PUBLIC HEALTH RELEVANCE: Treatment of schizophrenia and schizoaffective disorder frequently uses medications, such as benzodiazepines(BDZ), to treat negative affects, such as anxiety, that often accompany psychosis. Modulation of the GABA system by BDZ is potentially relevant to the pathophysiologyof schizophrenia, since dysfunction of the GABA system has been identified in post-mortem work. This project will use functional neuroimaging to identify networks changed by BDZ while schizophrenia patients process negative emotional material, knowledge that may lead to the design of better treatment interventions for this devastating illness.